Yamaoka Masaya, Maeda Norikazu, Takayama Yasunori, Sekimoto Ryohei, Tsushima Yu, Matsuda Keisuke, Mori Takuya, Inoue Kana, Nishizawa Hitoshi, Tominaga Makoto, Funahashi Tohru, Shimomura Iichiro
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan.
PLoS One. 2014 Nov 14;9(11):e112813. doi: 10.1371/journal.pone.0112813. eCollection 2014.
Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.
内脏脂肪肥胖在代谢综合征的发生发展中起重要作用。我们之前报道了人类内脏脂肪肥胖对外周血细胞基因表达谱的影响。与昼夜节律相关的基因与内脏脂肪面积高度相关，周期同源物1（PER1）与内脏脂肪面积呈最显著的负相关。然而，脂肪组织中Per1的调控机制仍知之甚少。本研究旨在了解脂肪组织中Per1的调控机制。ob/ob小鼠在25周和35周龄时，脂肪组织中Per1 mRNA水平显著降低。在25周和35周龄时，ob/ob小鼠白色脂肪组织中其他核心生物钟基因的水平也较低。Per1 mRNA主要在成熟脂肪细胞部分（MAF）表达，在ob/ob小鼠的MAF中显著降低。为了研究可能的机制，用H2O2、肿瘤坏死因子-α（TNF-α）、S100A8和脂多糖（LPS）处理3T3-L1脂肪细胞。然而，这些试剂处理后未观察到Per1 mRNA水平有显著变化。将培养的3T3-L1脂肪细胞暴露于低温（33°C）会降低Per1和过氧化氢酶水平，并增加单核细胞趋化蛋白-1（Mcp-1）mRNA水平。低温还会使3T3-L1脂肪细胞中胰岛素介导的Akt磷酸化恶化。最后，遥测分析显示ob/ob小鼠脂肪组织温度较低。在肥胖状态下，脂肪组织低温似乎会加速脂肪细胞功能障碍。
